Kwon Se Jeong, Son Jinyoung, Chung Sang J
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
AbTis Company Ltd., 21, Geumhwa-ro 105beon-gil, Giheung-gu, Yongin 17073, Republic of Korea.
ACS Med Chem Lett. 2025 May 12;16(6):1131-1138. doi: 10.1021/acsmedchemlett.5c00178. eCollection 2025 Jun 12.
Nonsmall cell lung cancer (NSCLC) presents significant therapeutic challenges, causing advancements in targeted therapies. We have developed a site-selective antibody-drug conjugate (ADC), durvalumab-monomethyl auristatin E (MMAE), with a drug-antibody ratio (DAR) of 4, specifically targeting programmed death-ligand 1 (PD-L1), aimed at enhancing NSCLC therapy. Utilizing the innovative AbClick Pro linker, this ADC ensures stable, site-specific conjugation of MMAE to durvalumab, preserving antibody functionality and integrity. In vivo studies demonstrate that durvalumab-MMAE achieves substantial tumor growth inhibition in NSCLC xenograft models, with an impressive tumor growth inhibition rate of over 60% at lower dosages without significant toxicity. These results, combined with a favorable pharmacokinetic profile featuring extended half-life and low clearance, highlight the potential of durvalumab-MMAE (DAR4) as a potent next-generation ADC for treating PD-L1-expressing cancers, offering a promising avenue for improved NSCLC patient outcomes.
非小细胞肺癌（NSCLC）带来了重大的治疗挑战，推动了靶向治疗的进展。我们开发了一种位点选择性抗体药物偶联物（ADC），度伐利尤单抗-单甲基奥瑞他汀E（MMAE），药物与抗体比率（DAR）为4，特异性靶向程序性死亡配体1（PD-L1），旨在增强NSCLC治疗效果。利用创新的AbClick Pro连接子，这种ADC确保了MMAE与度伐利尤单抗的稳定、位点特异性偶联，保留了抗体的功能和完整性。体内研究表明，度伐利尤单抗-MMAE在NSCLC异种移植模型中实现了显著的肿瘤生长抑制，在较低剂量下肿瘤生长抑制率超过60%，且无明显毒性。这些结果，再加上具有延长半衰期和低清除率的良好药代动力学特征，突出了度伐利尤单抗-MMAE（DAR4）作为治疗PD-L1表达癌症的强效下一代ADC的潜力，为改善NSCLC患者的预后提供了一条有前景的途径。
